Medical diagnostic imaging has evolved as an important non-invasive tool for the evaluation of pathological and physiological processes. Presently, nuclear magnetic resonance imaging (MRI) and computerized tomography (CT) are two of the most widely used imaging modalities. Although both MRI and CT can be performed without the administration of contrast agents, the ability of many contrast agents to enhance the visualization of internal tissues and organs, as well as soft-tissue differentiation, has resulted in their widespread use.
Magnetic imaging agents, and the imaging moieties they are comprised of, typically are substances that have magnetic properties which cause the brightening or darkening of a magnetic resonance image. At least four broad MRI methodologies are currently being pursued; these are proton MRI, paramagnetic metal MRI, nitroxyl spin label MRI, and .sup.19 F MRI.
Fluorine (.sup.19 F) MRI is still in the early stages of development. However, because of the 100% natural abundance of .sup.19 F and the complete absence of biological background, .sup.19 F MRI promises to be an important diagnostic imaging tool of the future. For example, previously disclosed fluorine-containing imaging agents include: perfluoro-tert-butyl containing organic compounds (W. J. Rogers, Jr., et al., U.S. Pat. No. 5,116,599 issued 1992, U.S. Pat. No. 5,234,680 issued 1993, and U.S. Pat. No. 5,324,504 issued 1994); fluoro-substituted benzene derivatives (P. Blaszkiewicz et al., U.S. Pat. No. 5,130,119 issued 1992; M. T. Kneller et al., U.S. Pat. No. 5,318,770 issued 1993 and U.S. Pat. No. 5,385,724 issued 1994; R. T. Dean, U.S. Pat. No. 4,612,185 issued 1986); fluorine containing nitroxyl compounds (M. D. Adams et al., U.S. Pat. No. 5,362,477 issued 1994); fluorinated metal-chelating compounds and chelates (Daikin Kogyo KK, JP 6-136347 published 1994; Asai et al., EP 592306, published 1994; Imigawa et al., EP 603403; Green Cross Corp, JP 5-186372 published 1993); fluorinated fullerenes (W. P. Cacheris et al., U.S. Pat. No. 5,248,498); fluorene-amine compounds (W. H. Moos, U.S. Pat. No. 4,960,815 issued 1990 and U.S. Pat. No. 5,081,304 issued 1992); N-methyl-glucamine salts (G. B. Hoey et al., U.S. Pat. No. 4,639,364 issued 1987 and U.S. Pat. No. 4,913,853 issued 1990); fluorocarbons (D. M. Long, WO 89/03693 published 1989); perfluoro crown ethers (J. A. Rubertone et al., U.S. Pat. No. 4,838,274 issued 1989); perfluoro dioxolanes (H. -N. Huang et al., U.S. Pat. No. 5,070,213 issued 1991); perfluoro tert-butyl aryl compounds (A. Krishnan et al., U.S. Pat. No. 5,401,493, issued 1995); and perfluoro tert-butyl containing steroids (T. S. Everett et al., U.S. Pat. No. 5,397,563, issued 1995).
The inventors postulated that the targeting properties of fatty acids might be combined with the MRI properties of .sup.19 F to yield useful imaging agents. However, preliminary experiments revealed that aqueous solutions of fluorinated fatty acids, such as perfluoro-t-butyl-pentadecanoate (e.g., (CF.sub.3).sub.3 C--(CH.sub.2).sub.14 --COONa), were found to be toxic when administered intravenously to rats. The pH of an aqueous solution of a fluorinated fatty acid salt (Na.sup.+) is approximately 9.0. Upon adjusting the pH of the solution to near physiological values (pH about 7.5, thus forming the free acid), most of the fluorinated fatty acid precipitated out of solution. Therefore, the toxic effect was thought most likely to be due to precipitation of the fluorinated fatty acid in the blood.
The inventors subsequently discovered that the sulfonate derivatives of these fluorinated fatty acids (formed, by example, by reaction with an amino-sulfonic acid such as taurine, or with a hydroxy-sulfonic acid such as isethionic acid) may not only retain the useful fatty acid targeting properties and .sup.19 F magnetic resonance imaging properties of the simple fluorinated fatty acids, but also possess water solubilities which are relatively independent of pH. In effect, the acid function of the carboxylic acid group (with a pK.sub.a typically about 4.9) is replaced by a sulfonic acid group (with a pK.sub.a typically below about 2), thus offering improved water solubility and biocompatibility.
The salts of the fluorinated fatty acid sulfonate derivatives are water-soluble and will likely preferentially go to the kidneys. It can also be anticipated that, depending on the particular compound chosen as a contrast agent, and also its formulation, a good portion of the fluorinated fatty acid compounds go to the liver. For example, an emulsion may be prepared from a suitable oil and the desired fluorinated fatty acid sulfonate derivative (which may act as an emulsifier). Upon delivery to the liver, the amide or ester linkages of the fluorinated fatty acid sulfonates would be hydrolyzed. The freed fatty acids would then enter the fatty acid cycle; they would undergo enzymatic activation via mitochondrial, microsomal and peroxisomal carnitine acyltransferases and subsequently could be transported as acyl carnitines to the heart, where they would undergo .beta.-oxidation (see, e.g., Current Concepts in Carnitine Research, A. Lee Carter, ed., CRC Press, 1992). Remaining fluorinated acetic acid or similar short-chain oxidation products would finally be excreted by the kidneys, possibly in the form of acyl carnitines.